JPS61205208A - Rapidly solubilizing preparation for hard-soluble medicines - Google Patents

Abstract

PURPOSE:The title preparation that is obtained by adding hard-to-dissolve active ingredients and compounds selected from polyvinyl pyrrolidone, polyvinyl alcohol and so on to water and forcibly mixing them, thus markedly increasing dissolution speed of the hard-to-dissolve ingredients to take large advantage in producing the preparation. CONSTITUTION:Water or organic solvents are added to hard-to-dissolve medicines such as phenacetin or other anti-inflammatory, at least one selected from polyvinyl pyrrolidone, polyvinyl alcohol, methylcellulose, macrogol, hydroxyethylcellulose, hydroxypropylcellulose, gelatin and lactic acid and they are forcibly mixed with a roller mixer, as the solvent is vaporized off or the hard-to-dissolve medicine, and polyvinyl pyrrolidone and macrogol are forcibly kneaded. The organic solvent is most preferably ethanol.

Description

Detailed Description of the Invention "Field of Industrial Application" The present invention relates to a rapidly dissolving preparation of a poorly soluble drug and a method for producing the same, and more specifically to the bioavailability (b) of a poorly soluble drug.
ioavailability).
a) Either water or an organic solvent is added to a poorly soluble drug and a specific water-soluble polymer base, and the solvent is forcibly kneaded with a roll mixer while the solvent is volatilized.

Or (a) it relates to a fast-dissolving preparation of a poorly soluble drug, which is obtained by forcibly kneading a poorly soluble drug, polyvinylpyrrolidone, and macrogol in a roll mixer, and a method for producing the same.

[Background of the invention] For poorly soluble drugs, when administered orally.

It is difficult to absorb in the gastrointestinal tract, making it impossible to develop effective medicinal effects or achieve rapid efficacy. than before.

Increasing the solubility of poorly soluble pharmaceuticals is considered to be particularly important in increasing bioavailability and expecting effective drug efficacy and rapid efficacy, and various methods are known for improving solubility. For information on these methods, see Setsuo Yoshiyanagi,
area of chemistry.

31, 881 (1977) for details.

Currently, the methods that are attracting the most attention as methods for improving the solubility of poorly soluble drugs are the mixed pulverization method of poorly soluble drugs and a water-soluble polymer base, which is expected to have a mechanochemical effect;
A solvent method (also known as a coprecipitation method) in which a solid composition is obtained by using a water-soluble polymer as a base and then removing the solvent.

The material obtained by the coprecipitation method is called a coprecipitate).

However, all of these methods have advantages and disadvantages, and problems still remain in formulation.

That is, in the mixed pulverization method, 10 times or more of the base is required in order to amorphize a poorly soluble drug.

Since there are restrictions on the amount of drug that can be contained in a formulation, an increase in the size of the formulation is unavoidable, and there are other problems such as the need for a long time for pulverization. On the other hand, the coprecipitation method has the problem of residual solvents, and water cannot be used as a solvent for poorly soluble pharmaceuticals, and when the types of organic solvents are limited, there is a fear that they may have an adverse effect on living organisms.

As a result of our previous research on improving the dissolution rate of poorly soluble pharmaceuticals, the present inventors discovered that the combination of poorly soluble pharmaceuticals and a specific water-soluble polymer base,
We discovered a method of kneading with a roll mixer (hereinafter referred to as roll mixing method, sometimes referred to as dry roll mixing method) or a method of heating at a temperature below the melting point (hereinafter referred to as hot roll mixing method). 1 Japan reported that when using the roll mixing method, it was possible to obtain products with a significantly higher dissolution rate than those produced using the coprecipitation method, which was conventionally considered to be the best way to improve solubility. Proceedings of the 104th Annual Meeting of the Pharmaceutical Society of Japan, page 729 (1984)
Patent Application No. 59-45137].

However, according to subsequent research by the present inventors, although the roll-mixing method is an excellent method that can be used universally for most of various poorly soluble drugs, it is difficult to use roll-mixed powder samples of specific drugs such as griseofulvin and nifedipine. teeth,
Particularly when the water-soluble polymer content is low, the dissolution rate may not necessarily be clearly improved compared to a coprecipitate.

Improvement was needed.

[Structure of the Invention] In view of the above circumstances, the present inventors have made further intensive research into fast-dissolving formulations of poorly soluble pharmaceuticals.

A poorly soluble drug and a specific water-soluble polymer base are forcibly kneaded with a roll mixer while adding water or an organic solvent, or a poorly soluble drug, polyvinylpyrrolidone, and macrogol are forcibly kneaded with a roll mixer. The present invention was completed based on the finding that the preparation obtained by this process significantly increases the dissolution rate.

That is, one aspect of the present invention is (a) a poorly soluble pharmaceutical, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, macrogol, and hydroxyethylcellulose.

Hydroxypropylcellulose, carboxymethylcellulose, gum arabic, dextrin, gelatin.

One or two selected from the group consisting of pectin and lactose
or (b) a poorly soluble pharmaceutical, polyvinylpyrrolidone, and macrogol. A fast-soluble formulation of poorly soluble pharmaceuticals is made by forcibly kneading the above and the like using a roll mixer.

The purpose of this invention is to provide the preparation and its manufacturing method. The method of adding water or an organic solvent is hereinafter simply referred to as a semi-wet roll mixing method, and the method using polyvinylpyrrolidone and macrogol as a base is hereinafter simply referred to as a three-component roll mixing method, or as the case may be, a three-component dry roll mixing method.

(Poorly Soluble Drug) The poorly soluble drug used in the present invention refers to a drug that has low solubility in water and is poorly absorbed in the gastrointestinal tract when used as a typical oral preparation.

The semi-wet roll mixing method and the three-component roll mixing method of the present invention are particularly applicable to the preparation of griseofulvin, nifedipine, etc. as powder samples. The present invention is particularly useful for poorly soluble pharmaceuticals for which a simple dry roll mixing method cannot sufficiently improve solubility. However, the poorly soluble pharmaceuticals used in the present invention are not limited to the above-mentioned griseofulvin and nifedipine, but may be any drug that can be quickly dissolved by applying the present invention, and specifically, poorly soluble drugs such as phenacetii. antipyretic analgesics, poorly soluble non-steroidal anti-inflammatory drugs such as mefenamic acid and indomethacin, poorly soluble anticonvulsants such as phenytoin, poorly soluble inotropes such as dioquitoxin and digogycin, poorly soluble vasodilators other than nifedipine, Poorly soluble neuropsychiatric agents such as diazepam, cholic acid-based agents such as chenodeoxycholic acid or gallstone dissolving agents, steroid compounds such as prednisolone, cortiscin, hydrocortiscin, dexamethacin, and a wide range of poorly soluble drugs such as sulfa drugs and γ-tocopherol. Politics can also be applied.

(Water-soluble polymer base) As the water-soluble polymer base used in the semi-wet roll mixing of the present invention, the dissolution rate of poorly soluble pharmaceuticals can be improved by adding and kneading the water or organic solvent of the present invention. The specific water-soluble polymer base mentioned above can be mentioned.

In particular, polyvinylpyrrolidone, macrogol, and a mixture thereof, which are considered to impart lubricity and lower the surface tension of the powder surface through mechanical compaction, are most advantageous.

In the three-component roll mixing of the present invention, a mixed base of rufolivinylpyrrolidone and macrogol is used, which significantly enhances the rapid dissolution of nifedipine and griseofulvin. The reason why rapid dissolution can be achieved even in dry roll mixing is presumed to be due to the above-mentioned smoothness imparting (9) reduction in surface tension.

There are various types of water-soluble polymer bases with different molecular weights, and the intended purpose of the present invention can be achieved with any molecular weight, but if the molecular weight exceeds 100,000, the solubility will be slightly lower. Therefore, the base material preferably has a molecular weight of up to about 100,000.

Among these, polyethylene glycols having a molecular weight of up to 4000, which are liquid or low molecular weight solids, are advantageous.
1500 is most preferred.

Furthermore, although polyvinyl alcohol and the like in the base of the present invention can have any degree of saponification, the intended purpose of the present invention can be achieved, but those having a higher degree of saponification are relatively advantageous.

Further, the polymerization degree of the base is not an important rate-limiting factor in improving the dissolution rate, but as the degree of bipolymerization increases, the solubility gradually decreases, so those having a polymerization degree of up to 2000 are advantageously used.

(Addition of solvent) Semi-wet roll mixing is a method in which a solvent is added during forced kneading in a zero-roll mixer, the solvent is naturally volatilized during forced kneading, and finally the solid state is forcibly kneaded. [6ru. The reason why the formulation produced by semi-wet roll mixing is quick-dissolving is that the drug is suitably dispersed in the base by dissolving a portion of one or both of the poorly soluble drug and the base and melting due to the compaction of forced kneading. It is estimated that Therefore, the addition of a solvent (ie, water or organic solvent) in semi-wet roll mixing is not done to completely dissolve both the drug and the base as in the coprecipitation method.

The amount of solvent added may be an amount that dissolves a portion of the drug, the base, or both.9 According to experiments by the present inventors, the total amount of the drug and base is 5 g for both griseofulvin and nifedipine. If so, water.

For both ethanol, it has been found that a range of 2.5 ml to 7.5 ml is practically advantageous, and that 5 ml provides the highest dissolution rate.

The addition of the solvent is advantageously carried out by dry roll mixing for about 15 to 45 minutes, followed by gradual dropwise addition onto the rolls during forced kneading.

The organic solvent is not particularly limited as long as it has the property of dissolving a portion of one or both of the drug and the base and is volatilized without removing during kneading. However, in this semi-wet roll mixing, there is no problem of residual solvent in the conventional coprecipitation process.

Ethanol is most advantageous as organic solvent.

The ethanol may be aqueous ethanol.

In the semi-wet roll mixing of the present invention, the addition of water in particular brings about good results in rapid solubilization, something that was not found in conventional methods such as coprecipitation, and there is no problem with residual solvents, which is advantageous and unique. It is true.

(Roll mixer) The roll mixer used in the present invention consists of horizontal two-axis rolls, and the bulk powder is supplied between the rolls that rotate in a circle facing each other, and is a device that is kneaded by the rotation of the rolls. good.

This type of roll mixer is not currently available in medical formulation equipment (including laboratory use).

Although it is somewhat similar in shape to a roller converter, its purpose is completely different as it does not produce granules.

In the embodiment of the present invention, an open horizontal two-roll type mixing roll used for kneading and kneading such as mastication of rubber, which is widely used in the field of rubber industry, is used. A tray was installed to collect and re-supply the powder, and the rotation of the rolls was motorized.

In addition, in order to continuously produce the formulation or composition of the present invention, it is possible to automatically collect the powder that falls between the rolls, although this is not currently commercially available.

It is preferable to attach a refeeding device to the rollers, or to use a device that collects the kneaded material below the device by installing two horizontal rolls in multiple stages.

In addition, there is also a Pan Bali mixer that is not an open type roll mixer. This is designed for the purpose of kneading in a gas stream, and there is no need to use it for this purpose in the present invention. However, the roll mixer of the present invention handles powder, and scattering of powder during the formulation process is a problem, so it is not limited to an open type, but naturally includes a closed system device. .

The roll spacing is appropriately set in consideration of the conditions such as the poorly soluble drug used, the base material, and the dosage form, but it is usually 3/100 to 6.
It is set in the range of m/in and adjusted with a push boat. The material and hardness of the roll is chilled roll or made of nickel steel or hard chromium ore, with a Rockwell hardness of 70.
-65 degrees are commonly used and are also suitable for achieving the purpose of the present invention.

(Forced kneading) Forced kneading is an operation in which powder or granules or solids are strongly kneaded with liquids or highly viscous substances.

Finally, ultramicroscopic homogeneous mixing is performed.

The mechanical compaction effect of forced kneading dramatically increases the contact area between the drug and the base, and the surfactant effect of the base lowers the surface tension of the drug surface.

It is presumed that the dissolution rate of poorly soluble drugs is increased in order to improve so-called "wetting".

It is considered that in the semi-wet roll mixing of the present invention, the drug and base are better dispersed, and the compaction effect of the kneading is further enhanced.

Also, in the three-component roll mixing method of the present invention.

It is presumed that as a result of lowering the surface tension and improving "wetting", the dissolution rate was significantly enhanced compared to roll mixing of polyvinylpyrrolidone or macrogol alone.

The kneading time is set appropriately taking into consideration the production scale and conditions such as the poorly soluble drug and water-soluble polymer base used, but it is usually about 30 minutes to 3 hours for both semi-wet roll mixing and three-component roll mixing. That's enough.

As is clear from the experimental results of the present invention, sufficient effects can be achieved in all experimental systems in about one hour.

The blending ratio of the poorly soluble drug and the water-soluble polymer base or the three-component polyvinylpyrrolidone-macrogol varies mainly depending on the type of the poorly soluble drug, but the drug content can be at least 10% or more. In the semi-wet roll-mixed Nifidipine-polyvinylpyrrolidone system, a blending ratio of 1:1 shows the highest dissolution rate, and in the griseofulvin-polyvinylpyrrolidone system, a blending ratio of 3:1 shows the highest dissolution rate. Furthermore, in the case of three-component roll mixing, it is recognized that the optimum macrogol content is 10%.

A blending ratio of 9 goals of 16:74:10 shows the highest dissolution rate. However, the present invention is not limited to these blending ratios, and may be appropriately selected and set in consideration of the dissolution rate test results and other conditions.

(Formulation) The fast-dissolving preparation of the present invention can be prepared by (a) rolling mixing the drug and the base while adding a solvent and volatilizing it, or (b) mixing the drug and the polyvinylpyrrolidone macromolecule as described above. It is produced as a powder by roll mixing with gall.

This powder can be made into a powder as it is, but usually various additives for the formulation, such as fillers, binders, disintegrants, flavoring agents, and coloring agents, are added to this powder according to the dosage form.
This was prepared into powder, fine granules, granules, 9 tablets, and pills using conventional methods.

It is made into solid preparations for oral administration such as capsules.

[Effects of the Invention] The formulation of the present invention significantly increases the dissolution rate of poorly soluble pharmaceuticals. The experimental methods and results will be listed below to provide a detailed explanation of the present invention.

(Measurement of dissolution rate) 200 mg of the powder sample obtained in the example (100 meshes in total) was added to 36 water at 37 C with stirring, and the concentration of the dissolved poorly soluble drug was measured by passing it through a 10 mm flow cell using a spectrophotometer (Toshiba Beckman). , Specter 20), the absorbance at a characteristic wavelength was continuously recorded, and the dissolution rate was estimated from the slope of the obtained straight line.

This value was determined as the average value of five or more samples of the same sample.

(Experimental Results) (1) FIG. 1 shows the results of determining the dissolution rates of powder samples of various blending ratios of nifedipine-polyvinylpyrrolidone obtained in Examples 1 and 2. As a control, the compounding ratio of the drug of the same composition and the base was 100.
: O (nifezipi/single item).

A simple dry roll mixed powder sample was used.

As is clear from FIG. 1, the water and ethanol semi-wet roll mix of the present invention, the dry roll sample, especially the aqueous semi-wet roll mix sample of the present invention, exhibits a dissolution rate about 5 times that of the combined sample. In the case of ethanol, an even more remarkable improvement in dissolution rate was observed.

In particular, a remarkable increase in dissolution rate was observed when the nifedipine content was 50% and 75%. The respective dissolution rates of 50% and 75% are approximately 4 times higher than that of roll mixed samples and coprecipitate samples of the same composition.
It has reached 0 times and 20 times.

At least 18.7 mg,
A dissolution rate of /l-min or more is a value that could not be obtained with conventional products.

Figure 2 shows the results of determining the dissolution rates of powder samples with various blending ratios of polyvinylpyrrolitonone (2).As a control, the drug:base ratio of 10020 ( Griseofulvin alone).

92:8.84:16.75:25.66:34.50
:50.25 near 5, 16:84 and 9:91 dry roll mixed powder samples were used.

The results in Figure 2 show that this 25% semi-wet and dry roll mix
The dissolution rate of the conventional same composition was about 9 mg/l-m.
: A dissolution rate of n or more is a value that could not be obtained with conventional products.

(3) FIG. 3 shows the results of measuring the dissolution rates of dry roll mixed powder samples of nifedipine-polyvinyl biloride and non-macrogol obtained in Example 5 at various blending ratios. As a control, the ratio of drug: polyvinylpyrrolidone: macrogol was 6:4:1.
A ternary coprecipitate of 0.25:65:10.75:15:10 was used.

As is clear from this figure, macro goals 1500, 1
The ternary roll mix sample containing 0% nifudipine content exhibits significantly higher dissolution rates than the ternary coprecipitate over a wide range of about 10% to about 30% nifudipine content.

Especially at the nifudipine content of 16%, where the dissolution rate is maximum,
The value is about 4 times that of the control three-component coprecipitate sample, about 3 times that of the two-component roll mixed powder sample of nifudivin-polyvinylpyrrolid, and about 400 times that of nifedipine bulk powder.

(4) FIG. 4 shows the results of measuring the dissolution rates of powder samples of various blending ratios of the griseofulvin-polyvinylpyrrolidonomacrogol dry roll mixture obtained in Example 6.

As is clear from FIG. 4, the dissolution rate of the three-component roll mixture of griseofulvin-polyvinyl birrolidone macrogol increases over a wide range of griseofulvin contents. In particular, a ternary roll mixture with a griseofulvin/content of 16% exhibits a dissolution rate approximately four times higher than that of a griseofulvin/polyvinyl biloride/roll mixture and approximately twice as high as that of a coprecipitate.

As is clear from the above experimental results, the semi-wet roll mixing method and the three-component roll mixing method of the present invention.

It is the most superior method in terms of improving the dissolution rate.It further improves the dissolution rate and has greater advantages in formulation than the simple dry roll mixing method of two components.

This improvement in dissolution rate further promotes the surfactant action of the base, allowing the drug to be properly dispersed in the base and dramatically increasing the contact area between the drug and the base due to the compaction effect of forced kneading. It is presumed that this was brought about by a significant improvement in the "wetting" of the drug surface. In addition, amorphization due to drug kneading is based on crystal lattice misalignment [Example] Examples are listed below to explain in detail the drug and base that improve solubility, and means for improving solubility. . 2. As is clear from the above experimental examples, the present invention is a technology that can be generalized, and is not limited to only those described in the examples.

Example 1゜Nifedipine and polyvinylpyrrolidone [PVPK-
30, manufactured by Wako Tsumugiku ■] in an arbitrary weight ratio [75:2
5.50:5025 Near 5.16:84.9:91 ]
Weigh 5g of 5K, and add each unblended material to a plasti. Heat roll machine for kneading [The roll rotation of a horizontal two-roll kneader for laboratory use (mixing roll, manufactured by Eto Seisakusho) is motorized. rotates 1 to 2 times per second.
The material is fed onto horizontal filter rolls, and any material that falls between the rolls is collected on a tray.

While refeeding on a roll, mix by force for 30 minutes at room temperature), then add 5 g of drug base to the total amount of drug base.
ml of distilled water was gradually dropped onto the horizontal roll for an additional 30 ml.
Roll mix for a minute. Most of the added solvent G1 evaporates during about 20 minutes of roll mixing, and the final pressure becomes a solid mixture. This kneaded material was collected and dried under vacuum at room temperature for 3 hours to obtain a semi-wet roll mixture with a quantitative cl concentration.

The dissolution rate of this substance shows the value indicated by the roller in FIG. Further, the X-ray diffraction data of 50% polyvinylo II ton content is shown in FIG. The X-ray diffraction data and other physical and chemical properties of this product are almost the same as the Erol mixture.

Example 2゜ Distilled water in Example 1 was replaced with ethanol.

The rest was treated in the same manner as in Example 1 to obtain a kneaded product by semi-wet roll mixing of nifuzivin and polyvinylpyrrolidone in a ratio of 1:3, and dried and split in the same manner as in Example 1.

The dissolution rate of this product shows the values indicated by ○-○ in FIG.

Example 3 Griseofulvin and polyvinylpyrrolidone [PVP
K-30, Wako Tsumugi Co., Ltd. in an arbitrary weight ratio [9
2:8.84:16.75:25.66:34.50:
50°25Nia 5.16:84], and a kneaded product was prepared by semi-wet roll mixing with distilled water in the same manner as in Example 1.

The dissolution rate of this product shows the values shown in Figure 2 from opening to opening.

Example 4゜Griseofulvin and polyvinylpyrrolid/[PVP
K-30, manufactured by Wako Tsumugi Pharmaceutical ■] in an arbitrary weight ratio [8
4:16.80:20.75:25.70:30.66
:34°50:50.25Near 5.16:84, and then in the same manner as in Example 2, a kneaded product was prepared by semi-wet roll mixing of ethanol.

The dissolution rate of this product shows the values indicated by ◯ to ◯ in Figure 2.

Example 5 The macrogol content is 10%, and the weight ratio of nifedipine and polyvinylpyrrolid 7 [PVPK-30, N Hikari Pure Chemical Industries] is arbitrary [nifuzivin: polyvinylpyrrolidone: macrogol 9 = 81] =10, 16:74
:10.25:65:10.50:40:10.75:
15:10], weighed out so that the total weight was 5 g.

Each unblended material was mixed with a heated roll machine for plastic kneading [a laboratory horizontal two-roll kneader mixing roll (
Eto Seisakusho (manufactured by Eto Seisakusho) is supplied onto a horizontal roll that rotates 1 to 2 times per second, and any material that falls between the rolls is collected by catching it on a tray, and then returned to the roll. While supplying.

Knead for 1 hour at room temperature. The kneaded material was collected and dried under vacuum at room temperature for 3 hours to obtain a three-component roll mixture almost quantitatively.

The dissolution rate of this product shows the values shown in Figure 3 from mouth to mouth.

Example 6 The macrogol content was 10%, and griseofulvin and polyvinylpyrrolidone [pvp K-30, Wako Tsumugi Co., Ltd.] were mixed in an arbitrary weight ratio [griseofulvin/:polyvinylpyrrolidone macrogol in a ratio of 16:74:10] ．．
25:65:10.34:66:10.50:40:1
0゜66:34:10.75:15:10.84:6:
10] was weighed to give a total weight of 5 g, and treated in the same manner as in Example 5 to obtain a three-component roll mixture of griseofulvin almost quantitatively.

The solubility of this product is the value shown by the row in FIG.

[Brief explanation of the drawing]

FIG. 1 shows dissolution rate test results for a dry roll mixture of nifedipine-polyvinylpyrrolidone (control), a semi-wet roll mixture of water and ethanol. Figure 2 shows the dissolution rate test results for a griseofulvin-polyvinylpyrrolidone dry roll mixture (control), a semi-wet roll mixture of water and ethanol, and Figure 3 shows a ternary roll mixture of nifedipine-polyvinylpyrrolitone-macrogol. , a dissolution rate test result of a dry roll mixture of co-precipitated nifudivin-polyvinylpyrrolidone. Figure 4 shows the dissolution rate test results of griseofulvin-polyvinylpyrrolidone-macrogol mixture and griseofulvin-polyvinylpyrrolidone coprecipitate, and Figure 5 shows Example 1.
The X-ray diffraction patterns of the semi-wet roll mixtures of are shown, respectively.

Claims (4)

[Claims] (1) (a) poorly soluble pharmaceutical and polyvinylpyrrolidone,
One or more selected from the group consisting of polyvinyl alcohol, methylcellulose, macrogol, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, gum arabic, dextrin, gelatin, pectin, and lactose are added to water or an organic solvent. and (b) forcibly knead a poorly soluble drug, polyvinylpyrrolidone, and macrogol with a roll mixer while volatilizing the solvent, or (b) a fast-soluble preparation of a poorly soluble drug. (2) The poorly soluble drug is nifedipine, the nifedipine content is approximately 10% or more, and the dissolution rate is 18.7 mg/l・m
A fast-dissolving formulation of a poorly soluble pharmaceutical according to claim (1), which is (3) The poorly soluble drug is griseofulvin, the griseofulvin content is 92% or less, and the dissolution rate is 9 mg/l・m
A fast-dissolving formulation of a poorly soluble pharmaceutical according to claim (1), which is (4) (a) poorly soluble pharmaceutical and polyvinylpyrrolidone,
One or more selected from the group consisting of polyvinyl alcohol, methylcellulose, macrogol, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, gum arabic, dextrin, gelatin, pectin, and lactose are added to water or an organic solvent. and (b) forcibly kneading the poorly soluble pharmaceutical, polyvinylpyrrolidone, and macrogol with a roll mixer while volatilizing the solvent. Manufacturing method for fast-dissolving preparations